The present invention relates to amide derivatives of 1,4-di-substituted piperidines useful in the treatment of cognitive disorders, pharmaceutical compositions containing the compounds, methods of treatment using the compounds, and to the use of said compounds in combination with acetylcholinesterase inhibitors.
Alzheimer's disease and other cognitive disorders have received much attention lately, yet treatments for these diseases have not been very successful. According to Melchiorre et al. (J. Med. Chem. (1993), 36, 3734-3737), compounds that selectively antagonize M2 muscarinic receptors, especially in relation to M1 muscarinic receptors, should possess activity against cognitive disorders. Baumgold et al. (Eur. J. of Pharmacol., 251, (1994) 315-317) disclose 3-.alpha.-chloroimperialine as a highly selective m2 muscarinic antagonist.
Piperidine-derivative muscarinic antagonists useful in the treatment of cognitive disorders such as Alzheimer's disease are disclosed in WO96/26196 and WO98/05292. In particular, WO98/05292 discloses compounds of the generic formula ##STR3##
wherein, inter alia, Y is CH; Z is N; X is --SO.sub.2 --; R is substituted phenyl; R.sup.1 and R.sup.21 are each H, or together form an ethylenedioxy group; R.sup.3, R.sup.4, R.sup.26 and R.sup.27 are hydrogen; and R.sup.2 is a N-substituted 4-piperidine derivative, wherein the N-substituent can be an amino-substituted benzoyl or pyridinecarboxyl group. Similar compounds wherein the benzene ring is replaced by a pyridinyl ring are disclosed in PCT/US99/12821. Compounds of the present invention represent a selection invention over WO98105292 and PCT/US99/12821.